Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
  • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
  • C07D495/04—Ortho-condensed systems

Definitions

• the present invention relates to a process for preparing (+)-(S)-alpha-2-(chlorophenyl)- 6,7-dihydrothieno [3,2-C] pyridine-5-(4-H)-acetic acid methyl ester hydrogen sulphate of Formula I, commonly known as Clopidogrel bisulphate in "Form-I" crystalline form.
• the present invention further relates to improvements in the preparation of clopidogrel free ba ⁇ e and process for recovery and recycling of resolving agent camphor sulphonic acid.
• Clopidogrel is known for its platelet aggregating and anti-thrombotic properties and finds medicinal applications in this field. It can be represented by Formula-I, and was disclosed in Patent US 4529596 (hereinafter referred as '596' patent) in its racemic form for the first time.
• clopidogrel free base The pure dextrorotatory isomer of clopidogrel (herein after referred as clopidogrel free base) was released from the respective diastereomeric salt by reaction with sodium bicarbonate in an aqueous solvent followed by extractive work-up.
• the starting racemic clopidogrel free base was obtained from hydrogen sulphate salt of racemic clopidogrel by following an aqueous treatment in presence of bicarbonate.
• Clopidogrel free base was then converted into its hydrogen sulfate salt by dissolving in acetone, cooling and mixing with concentrated sulfuric acid to precipitation.
• '459 patent did not characterize or suggest any name to this crystals (polymorph) of Clopidogrel hydrogen sulfate.
• Clopidogrel hydrogen sulfate according to example IA of the '915 patent describes the introduction of Clopidogrel camphor sulfonate in methylene dichloride (MDC) and transformation of salt into the clopidogrel base with potassium carbonate in aqueous conditions.
• MDC methylene dichloride
• Clopidogrel base is extracted in MDC and solvent is evaporated. Residue obtained is dissolved in acetone and cooled. Addition of sulfuric acid to said solution precipitate out Clopidogrel hydrogen sulfate in Form -I.
• Form-II either by keeping mother liquor of Form-I for prolonged periods or by heating the acetone solution containing the base after addition of sulfuric acid to reflux or by subjecting the suspension to mechanical shearing using a shearing device or by inoculation.
• the present inventors have also noted that, since the Form I is thermodynamically unstable, the process variants of dissolving clopidogrel hydrogen sulphate salt in conventional solvents at higher temperature and cooling to precipitate Form I resulted in Form II or its mixture with Form I. Moreover, the poor solubility of clopidogrel salt (whereas the free base possess good solubility) in most of the known solvents does not allow to use this crystallization process variant to be practiced.
• WO2005003139 patent discusses combination of polar and non-polar solvent combinations for obtaining Form I, however, the present inventors have found that the adjustment of specific proportion of two or more solvents are rather difficult and does not give consistent & reproducible results while adjusting the polarity of mixtures.
• WO2004074215 disclosed a racemization process for R-clopidogrel acid salt using liquor ammonia and finally aqueous extractive work-up to isolate the clopidogrel free base.
• a parallel publication, WO/2004/108665 on process for clopidogrel has used an aqueous extractive work-up to isolate clopidogrel free base from it's acid salt.
• Another patent application No.WO/2007/032023 also discloses ammonia for basification of clopidogrel salt using an aqueous extractive work-up to produce clopidogrel free base.
• Clopidogrel free acid of Formula X which needs to be monitored in the active substance as per pharmacopoeia] specification.
• the main cause of generation of this impurity in clopidogrel is the hydrolysis of methyl ester under aqueous conditions during the processing.
• An objective of the present invention is to provide solvent systems where the Form I crystals of clopidogrel hydrogen sulphate can be efficiently and reproducibly formed and easily maneuvered at large scale operations.
• the present invention provides solvent(s) or solvent systems useful for making Form I clopidogrel hydrogen sulphate (Formula IB) in a consistent & reproducible manner and processes for the same.
• the present invention provides an improved industrial process for crystallizing out polymorph 'Form I' of (+) clopidogrel hydrogen sulphate (also called clopidogrel hydrogen sulphate or clopidogrel bisulphate) from a Type -I organic solvent or liquid comprising two or more functional groups with a proviso that at least one functional group is different from each other; or from a Type-II solvent and/or solvent mixture selected from methyl ethyl ketone, cyclopentylmethyl ether, dipropylglycolether, dibutylglycol ether, propylmethyl cellosolve, butylmethylcellosolve, propylethylellosolve, butylethylcellosolve or their mixtures, in a reproducible manner without detectable contamination of form II.
• Type-I solvent examples of multiple functional groups which can be present in the Type-I solvent are selected from those of ketone-ester, ether- ketone, nitrile-ester, alcohol-ester, alcohol-ether, ketone- ether, halogen substituted esters, nitro-esters, ketone-nitrile etc.
• Especially preferred Type-I solvents possess carbon atoms ranging from C4 to C 12 atoms, specific examples of such solvents are ethyl acetoacetate, methyl acetoacetate, chloropropionyl acetate, alkyl lactates, chloroethylacetoacetate, chloroacetylacetoacetate etc.
• the process for preparation of 'Form P comprises dissolving the clopidogrel hydrogen sulphate of any crystal form, for example, amorphous, Form II, or Form III, or their mixtures or contaminated Form I of clopidogrel hydrogen sulphate in a suitable multifunctional group solvent (Type-I) as defined above; then cooling the obtained clopidogrel hydrogen sulphate solution to a temperature of -20 to 30° C and maintaining the salt at a temperature of about 10 to 30 ° C to complete precipitation of Form I and filtering the crystals of Form I obtained.
• the present invention provides an improved process for preparing clopidogrel free base from its acid addition salt.
• the present process comprises the step of treating clopidogrel acid salt in non-aqueous conditions using ammonia to obtain clopidogrel in free base form.
• the process according to the invention comprises treating clopidogrel acid salt, for example, bisulphate, hydrochloride, hydrobrmomide, camphorsulphonate salt or similar salts with ammonia in a non-aqueous solvent.
• clopidogrel acid salt for example, bisulphate, hydrochloride, hydrobrmomide, camphorsulphonate salt or similar salts
• ammonia for example, bisulphate, hydrochloride, hydrobrmomide, camphorsulphonate salt or similar salts.
• the present invention provides an efficient process to recover and recycle camphor sulphonic acid after its use in the resolution of a racemic substrate, for example, ( ⁇ )-clopidogrel, comprises: a) treating the diastereomeric camphor sulphonate salt of substrate with ammonia in a non-aqueous reaction solvent; b) separating the ammonium camphor sulphonate salt from the substrate; c) treating said ammonium camphor sulphonate salt with an acid in non-aqueous solvent to exchange the ammonium ion with the acid to free camphor sulphonic acid; and d) isolating free camphor sulphonic acid from the reaction for recycling.
• Figure 1 represents Powder X-Ray diffraction pattern (PXRD) of clopidogrel hydrogen sulphate Form I prepared according to example 1 of the present invention.
• Figure 2 represents Differential Scanning Calorimetry record of Form I of clopidogrel hydrogen sulphate prepared according to example 1 of the present invention.
• Figure 3 represents Powder X-Ray diffraction pattern (PXRD) of clopidogrel hydrogen sulphate Form I standard as given in '915 patent.
• PXRD Powder X-Ray diffraction pattern
• Figure 4 represents the spectrogram obtained by Fourier Transform Infra Red spectrometry (FTIR) of clopidogrel hydrogen sulphate Form I prepared according to example 1 of the present invention.
• FTIR Fourier Transform Infra Red spectrometry
• Figure 5 represents an overlay of powder x-ray diffraction pattern (PXRD) of clopidogrel hydrogen sulphate crystalline Form I and Form II.
• PXRD powder x-ray diffraction pattern
• any of the words “including,” “includes,” “comprising,” and “comprises” mean “including without limitation” and shall not be construed to limit any general statement that it follows to the specific or similar items or matters immediately following it.
• Embodiments of the invention are not mutually exclusive, but may be implemented in various combinations. The described embodiments of the invention and the disclosed examples are given for the purpose of illustration rather than limitation of the invention as set forth the appended claims.
• isolated is used to indicate separation or collection or recovery of the compound being isolated in the specified crystalline form.
• separating from a solvent with respect to the crystalline solids described herein means obtaining a solid of specified characteristics from a solution or a partial solution.
• treating means adding or combining or mixing the stated reagent or materials to the things being treated.
• (+)-clopidogrel or "(+)-(S)-clopidogrel” means the dextrorotatory isomer of clopidogrel.
• the name "Clopidogrel hydrogen sulphate” or “clopidogrel bisulphate” used means the compound represented in formula IB.
• the term “forming a solution” means obtaining a solution of a substance in a solvent in any manner.
• non-aqueous medium means a solvent medium that does not contain water in significant amounts.
• the term does not exclude solvents containing insignificant amounts of water, which may be less than 5%, more preferably less than 2%.
• inoculating has the same meaning as the term “seeding,” and means adding previously obtained solid to facilitate crystallization.
• seeding crystals with respect to claimed process means inoculating crystals/powder of previously obtained crystalline Form I of clopidogrel hydrogen sulphate.
• crystalline Form I or "Form I" of clopidogrel hydrogen sulphate is the polymorphic form denoted as Form I and having characteristics as given in US6429210 patent.
• Identification of solids obtained by the process of the invention can be made by comparing with the reference analytical information provided in the US6429210 patent.
• operator, instrument and other similar variables may result in some margin of error with respect to analytical characterization of the solid.
• the present inventors on exploring various process alternatives, for a reliable process solution have found that the use of selected organic solvents which are categorized into either Type-I or Type-Il solvents, wherein the Type -I organic solvent possesses two or more functional groups, wherein at least one such functional group is distinctly different from other or the cross mixtures of such solvents; and the Type-ll solvent is a solvent selected from methyl ethyl ketone, cyclopentylmethyl ether, dipropylglycol ether, dibutylglycol ether, propylmethyl cellosolve, butylmethylcellosolve, propylethylellosolve, butylethylcellosolve or their mixtures, for crystallization of clopidogrel permits reliable preparation of Form I of clopidogrel hydrogen sulphate.
• Especially preferred functional groups in the Type-I solvent are either ester-ketone, or ether-ketone, or hydroxyl -esters, keto-esters, or ester-nitrile, or ether-ester, or nitro-esters etc.
• Especially preferred Type-I solvent has carbon atoms from C4 to C12 in the molecule.
• the preferred Type-I solvents are ethyl acetoacetate, methyl acetatoacetate, alkyl lactate, chloropropylacetate esters. 4-chloroethylacetoacetate esters, chloroacetyl acetoacetate esters etc.
• a solvent selected from the group of esters, C3-C6 aliphatic or alicylcic ketones, C3-C6 chain or branched chain alcohols, and ethers in about 1 to 25 weight percent in the Type-I (possessing multi-functional group) or Type-II solvents of the present invention gives Form I consistently. The weight percent will depend upon the choice of the individual solvent from the above class of solvents, but can be determined by routine experimentation.
• Especially preferred solvents for making mixtures are acetone, methylpropyl ketone, methylisopropyl ketone, isobutyl ketone among ketones; propylacetate and butyl acetate among esters; butanol and pentanol among alcohols; and tertiary butyl methyl ether and cyclopentyl methyl ether among ethers.
• Most of these other solvents are not suitable independently for preparing pure Form I.
• the presence of these solvents in the process of the present invention are especially useful in removing the solvents of multiple functional groups used in the invention to keep their level in the final product as low as possible to meet the pharmacopoeias specifications. It is very surprising to note that the reactive compounds like ethyl acetoacetate is inert through out the crystallization process of the present invention and does not participate in any significant chemical change or impurity formation as against the expected reactivity of such solvents.
• the precipitated crystals may be collected by conventional methods like filtration or centrifugation. Although temperature lower than -20 ° C also works while addition of sulfuric acid, owing to the industrial applicability the above range is preferred.
• Type-I or Type-II solvents can be mixed with each other and may be employed in all proportions.
• the preferred concentration of sulphuric acid is in the range of 80% to 98% and the molar ratios are in the range of 1 to 1.1 with respect to the (+)-clopidogrel base.
• the most preferred concentration of sulphuric acid used in the salt formation is 90-98%.
• the sulphuric acid may be employed directly in the salt formation or may be employed as a solution in a carrier solvent.
• Especially preferred carrier solvents although not limited to, are those selected from the above described Type-I or Type-II group solvents.
• the exotherm of sulphuric acid addition is controlled by cooling and maintaining the temperature in between -10 to 10 0 C.
• the Form I so obtained was characterized by PXRD, DSC and FTIR without any detectable quantity of Form II or other polymorphic Forms with respect to the standard PXRD pattern of Form I as described in '915 patent.
• the Form-1 obtained by the process of the present invention does not contain any detectable Form-II polymorph and therefore it is stable to storage/handling.
• the clopidogrel free base solution may be obtained by dissolving clopidogrel free base in the solvent at any temperature at or below the reflux temperature of the solvent and the solution may then be filtered to remove any particulate matter.
• the solution of the clopidogrel free base is obtained, the solution is cooled to a temperature below 25 degree, more particularly below 10 degrees and sulpuric acid solution is incorporated to form the clopidogrel hydrogen sulphate salt.
• the mass is then cooled or maintained at this temperature until crystallization of the solid is complete. The solid is filtered, washed, and dried.
• the solution may be seeded (inoculated with seed crystals) with previously obtained crystals of the Form I.
• the seed crystals may be obtained by performing the present invention at a lower scale or by methods known in the art. The process conditions are further illustrated in the Examples.
• a process for preparation of 'Form F comprises dissolving the clopidogrel hydrogen sulphate salt of any crystal form (for example, amorphous, Form II, or Form III, or their mixtures or contaminated Form I in a Type-I organic solvent containing suitable multi-functional group as discussed above, for example, ethyl acetoacetate or alky! lactate, or chloroethylacetoacetate, then cooling the obtained clopidogrel hydrogen sulphate solution to a temperature of -20 to 30° C and maintaining the salt at a temperature of about 10 to 30 ° C to complete precipitation of Form I and filtering the crystals of Form I obtained.
• any crystal form for example, amorphous, Form II, or Form III, or their mixtures or contaminated Form I
• a Type-I organic solvent containing suitable multi-functional group as discussed above, for example, ethyl acetoacetate or alky! lactate, or chloroethylacetoacetate
• the dissolution of the clopidogrel salt in the solvent is carried out at a temperature from ambient to reflux temperature of the solvent, preferably from 50 to reflux temperature of the solvent.
• the solution is then allowed to cool to room temperature, optionally kept for a holding time and then cooled to 0 to 5 degree to precipitate the Form I clopidogrel hydrogen sulphate.
• the starting material, clopidogrel free base may be obtained by following any known process disclosed in the literature.
• the present inventors provide an efficient process to obtain clopidogrel free base from an acid addition salt, especially camphor sulphonate salt of clopidogrel, wherein said process essentially gives better purity & economy, handling and recyclability of resolving agent.
• an improved synthesis of Clopidogrel is provided by reacting clopidogrel acid salt using ammonia in non-aqueous conditions to obtain clopidogrel in free base form.
• the reaction is performed in presence of an organic solvent. It should be understood that the present process is applicable to racemic clopidogrel as well as enantiomers of clopidogrel in any acid salt form.
• the clopidogrel acid salts may be selected from known ones, for example bisulphate, hydrochloride, hydrobromide, naphthalene sulphonate, methane sulphonate, camphor sulphonate, tartarate etc.
• the ammonia may be employed in gaseous form or as a solution in suitable non-aqueous organic solvent.
• the organic solvent may be selected from any inert solvent, where a difference of solubility of ammonium salt and clopidogrel salt can be attained.
• solvents include, but not limited to, hydrocarbons, such as toluene, dichloromethane, dichloroethane, alcohols such as isopropanol, ethanol, ketones such as acetone, methyl ethylketone, Methylisobutyl ketone, methylpropylketone, etc., and ethers such as diisopropyl ether, diglyme, ter.butylmethyl ether, cyclopentylmethyl ether etc
• the clopidogrel acid salt is reacted with ammonia gas in an organic solvent.
• the process is accomplished by making a solution or suspension of clopidogrel acid salt in an organic solution and passing ammonia gas to attain a constant pH in the range of about 8 to 9.
• an ammonia solution prepared in an organic solution (by passing ammonia into a neat solvent) may be added to a solution/suspension of clopidogrel salt in organic solvent or vise versa.
• the reaction may be conducted at room temperature, but preferably under cooling to control the exothermicity. While progressing the reaction the ammonium salt separates out from the organic solution and clopidogrel free base remain in solution in the organic solvent in stable form.
• the ammonium acid salt of camphor sulphonic acid may be conveniently removed/recovered from the reaction by simple filtration.
• the clopidogrel free base from the mother liquor is recovered after filtering out the ammonium salt of the camphor sulphonic acid from the organic solvent, followed by elimination of solvent.
• the yield of either clopidogrel free base or ammonium camphor sulphonate is nearly quantitative, whereas in conventional method it is about 75-90%.
• the starting clopidogrel acid salt may be obtained by following any conventional methods.
• the (S)-clopidogrel (L)-camphor sulphonate salt or bisulphate salt is used.
• (S)-clopidogrel (L)-camphor sulphonate salt is preferably obtained after resolution of racemic clopidogrel into it enantiomers using optically active camphorsulphonic acid.
• the process of resolution involves contacting Clopidogrel base with (-) camphor sulphonic acid in acetone or a mixture of polar and non-polar/weakly polar organic solvents and crystallizing the camphor sulphonic salt of (S)-clopidogrel according to our parent application publication number WO/2005/104663.
• the unwanted isomer, as (-) (R)- clopidogrel camphor sulphonate salt, left behind in the mother liquor is also treated with ammonia as described above to recover ammonium camphor sulphonate, and thereafter racemized and recycled by treatment with NaOH in alcoholic solvents like methanol at a temperature ranging from 30 to 5O 0 C to obtain a 50:50 ratio of both isomers (referred as racemic mixture) as exemplified in the parent application.
• the present invention provides an efficient process to recover and recycle camphor sulphonic acid after its use in the resolution of a racemic substrate, for example, ( ⁇ )-clopidogrel, comprises: a) treating the diastereomeric camphor sulphonate salt of substrate with ammonia in a non-aqueous reaction solvent; b) separating the ammonium camphor sulphonate salt from the substrate; c) treating said ammonium camphor sulphonate salt with an acid in non-aqueous solvent to exchange the ammonium ion with the acid to free camphor sulphonic acid; and d) isolating free camphor sulphonic acid from the reaction for recycling.
• the recovery and recycling of camphorsulphonic acid comprises treating ammonium camphorsulphonate, obtained after following step (a) and (b) as illustrated for clopidogrel hereinbefore, in an organic solvent with an acid to liberate free camphor sulphonic acid and the by-product ammonium salt is removed by simple filtration.
• ammonium camphor sulphonate salt was suspended or dissolved in an organic solvent for example, but limited to toluene, ethanol, isopropanol, acetone, methylethylketone, and treated with Hydrochloric acid, preferably in gaseous form or as a solution on organic solvent like Isopropanol until the salt exchange is completed.
• the free Camphor sulphonic acid can be isolated by filtering out the precipitated ammonium chloride and solvent elimination, followed by optional crystallization.
• the free Camphor sulphonic acid obtained after filtering out the precipitated ammonium chloride may be directly used as a solution, without further isolation, for resolution of clopidogrel, if the solvent is acetone or its mixtures with other solvents like dichloromethane.
• Analytical characterization of the solid(s) obtained in accordance with the process of the invention was carried out by using X-ray powder diffraction using a PANALYTICAL XpertPRO X-Ray machine of Philips make.
• the X-ray powder diffraction patterns were recorded with Cu K alpha-1 radiation source (voltage of 50 kV; current: 25 mA).
• the stable Clopidogrel bisulphate Form I obtained by the process of the present invention may be formulated into a dosage form, e.g., tablet, capsule, etc., by combining with one or more pharmaceutically acceptable excipients using known techniques.
• the resulting dosage form may include a suitable amount of the active ingredient required for the desired action. Further, the dosage form may be immediate release or extended release.
• Clopidogrel base (5.5 g) was dissolved in propylmethyl cellosolve (40 ml) at room temperature. This mixture was cooled to -10° C and concentrated sulphuric acid (1.1 ml) (90%) was added maintaining temperature -10° to 0° C while addition. The reaction mass was stirred for 1.0 hour and warmed slowly to 15 to 20° C in 2 hours. The formed crystals were stirred for 3 hour. The reaction mass temperature was further raised to 28 to 30°C and maintained for 8.0 hour. The solid obtained was filtered under suction and washed with acetone, and dried in oven at 48° C for 3 hour. The solid after drying weighed 5.9 g was Form 1 clopidogrel hydrogen sulphate (PXRD pattern is identical with figure 1).

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• 2008
  • 2008-01-29 WO PCT/IN2008/000052 patent/WO2008093357A2/en active Application Filing
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• 2009
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